Mapping of hereditary mixed polyposis syndrome (HMPS) to chromosome 10q23 by genomewide high-density single nucleotide polymorphism (SNP) scan and identification BMPHR1A loss of function

Journal of Medical Genetics (Impact Factor: 6.34). 04/2006; 43(3):e13. DOI: 10.1136/jmg.2005.034827
Source: PubMed


Hereditary mixed polyposis syndrome (HMPS) is characterised by colonic polyps of mixed histological types that are autosomal dominantly inherited and eventually lead to colorectal cancer (CRC). Study of the molecular basis of HMPS will enhance our knowledge of the genetic basis of the mixed polyposis-carcinoma sequence in both hereditary and sporadic CRC.
We performed a genomewide linkage search on 15 members of a three-generation HMPS family using the GeneChip Human Mapping 10K Array and identified a 7 cM putative linkage interval on chromosome 10q23. Subsequently, 32 members from two HMPS families were typed with nine microsatellite markers spanning the region and the linkage was confirmed with a maximum multi-point logarithm of the odds (LOD) score of 4.6 (p<0.001). The 10q23.1-10q23.31 haplotypes segregate with the disease in both families. We screened for mutations in four candidate genes within the linkage region and identified an 11 bp deletion in the bone morphogenesis protein receptor 1A (BMPR1A) gene in one family.
Our results indicate that BMPR1A mutation accounts for HMPS. The data suggest that inactivating BMPR1A can initiate colorectal tumourigenesis via the mixed polyposis-carcinoma sequence.

Download full-text


Available from: Pehyean Cheah, Jul 27, 2015
  • Source
    • "The genetic cause (s) of HMPS remains elusive. HMPS has been mapped to the chromosomal region of 10q23, which includes BMPR1A[50] and O’Riordan et al. found a BMPR1A mutation in one family [51]. Jaeger et al. reported that a duplication in the 3’ end of the SCG5 gene and a region upstream of GREM1-locus can cause HMPS [49]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hamartomatous Polyposis Syndromes (HPS) are genetic syndromes, which include Peutz-Jeghers syndrome, Juvenile polyposis syndrome, PTEN hamartoma tumour syndrome (Cowden Syndrom, Bannayan-Riley-Ruvalcaba and Proteus Syndrome) as well as hereditary mixed polyposis syndrome. Other syndromes such as Gorlin Syndrome and multiple endocrine neoplasia syndrome 2B are sometimes referred to as HPS. HPS is characterized by the development of hamartomatous polyps in the gastrointestinal tract as well as several extra-intestinal findings such as dermatological and dysmorphic features or extra-intestinal cancer. The syndromes are rare and inherited in an autosomal dominant manner. The diagnosis of HPS has traditionally been based on clinical criteria, but can sometimes be difficult as the severity of symptoms range considerably from only a few symptoms to very severe cases - even within the same family. De novo cases are also frequent. However, because of the discovery of several associated germline-mutations as well as the rapid development in genetics it is now possible to use genetic testing more often in the diagnostic process. Management of the syndromes is different for each syndrome as extra-intestinal symptoms and types of cancers differs. Clinical awareness and early diagnosis of HPS is important, as affected patients and at-risk family members should be offered genetic counselling and surveillance. Surveillance in children with HPS might prevent or detect intestinal or extra-intestinal complications, whereas in adulthood surveillance is recommended due to an increased risk of cancer e.g. intestinal cancer or breast cancer.
    Orphanet Journal of Rare Diseases 07/2014; 9(1):101. DOI:10.1186/1750-1172-9-101 · 3.36 Impact Factor
  • Source
    • "In the father they included metaplastic polyps and adenomas, in the son juvenile polyps were additionally diagnosed. In the most accurate way clinical traits of mixed polyposity syndrome were presented in a family of a few generations, termed SM96 [45,46]. Among more than 200 members of the family 42 individuals demonstrated the presence of various types of polyps, ranging from tubular adenomas, papillary adenomas, flat adenomas to hyperplastic polyps and atypical juvenile polyps. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hamartomas are tumour-like malformations, consisting of disorganized normal tissues, typical of the site of tumour manifestation. Familial manifestation of hamartomatous polyps can be noted in juvenile polyposis syndrome (JPS), Peutz-Jeghers' syndrome (PJS), hereditary mixed polyposis syndrome (HMPS) and PTEN hamartoma tumour syndrome (PHTS). All the aforementioned syndromes are inherited in an autosomal dominant manner and form a rather heterogenous group both in respect to the number and localization of polyps and the risk of cancer development in the alimentary tract and other organs. Individual syndromes of hamartomatous polyposis frequently manifest similar symptoms, particularly during the early stage of the diseases when in several cases their clinical pictures do not allow for differential diagnosis. The correct diagnosis of the disease using molecular methods allows treatment to be implemented earlier and therefore more effectively since it is followed by a strict monitoring of organs that manifest a predisposition for neoplastic transformation.
    Hereditary Cancer in Clinical Practice 06/2013; 11(1):4. DOI:10.1186/1897-4287-11-4 · 1.47 Impact Factor
  • Source
    • "The conditions juvenile polyposis syndrome (JPS) and hereditary mixed polyposis syndrome (HMPS) are associated with an increased risk of colorectal carcinoma. Mutations in the BMPR1A gene have been identified in up to 20% of patients with JPS [31,32], and HMPS has also been associated with mutations in the BMPR1A gene [33]. BMPR1A has also been reported to be a tumor suppressor in skin tumorigenesis [16]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Neurotrophic factors such as brain derived neurotrophic factor (BDNF) are synthesized in a variety of neural and non-neuronal cell types and regulate survival, proliferation and apoptosis. In addition, bone morphogenetic proteins (BMPs) inhibit the proliferation of pulmonary large carcinoma cells bone morphogenetic protein receptor, type IA (BMPR1A). Little is known about the expression of BDNF or BMPR1A in malignant gall bladder lesions. This study was to evaluate BDNF and BMPR1A expression and evaluate the clinicopathological significance in benign and malignant lesions of the gallbladder. Methods The BDNF and BMPR1A expression of gallbladder adenocarcinoma, peritumoral tissues, adenoma, polyp and chronic cholecystitis were Immunohistochemically determined. Results BDNF expression was significantly higher in gallbladder adenocarcinoma than in peritumoral tissues, adenoma, polyps and chronic cholecystitis samples. However, BMPR1A expression was significantly lower in gallbladder adenocarcinoma than in peritumoral tissues, adenomas, polyps and chronic cholecystitis tissues. The specimens with increased expression of BDNF in the benign lesions exhibited moderate- or severe-dysplasia of gallbladder epithelium. BDNF expression was significantly lower in well-differentiated adenocarcinomas with maximum tumor diameter <2 cm, no metastasis to lymph nodes, and no invasion of regional tissues compared to poorly-differentiated adenocarcinomas with maximal tumor diameter >2 cm, metastasis of lymph node, and invasiveness of regional tissues in gallbladder adenocarcinoma. BMPR1A expression were significantly higher in the well-differentiated adenocarcinoma with maximal tumor diameter <2 cm, no metastasis of lymph node, and no invasion of regional tissues compared to poorly-differentiated adenocarcinomas with maximal tumor diameter >2 cm, metastasis of lymph node, and invasiveness of regional tissues in gallbladder. Univariate Kaplan-Meier analysis indicated increased expression of BDNF or decreased expression of BMPR1A was associated with decreased disease specific survival (DSS) rates. Similarly, multivariate Cox regression analysis showed increased expression of BDNF or decreased expression of BMPR1A are independent predictors of poor DSS rates in gallbladder adenocarcinoma. Conclusions In gallbladder malignancies, the increased expression of BDNF and decreased expression of BMPR1A were associated with increased risk of metastasis, regional invasion and mortality. They might serve as novel indicators of gallbladder adenocarcinoma outcomes, which may prove valuable for the development of personalized therapeutic paradigms.
    World Journal of Surgical Oncology 03/2013; 11(1):80. DOI:10.1186/1477-7819-11-80 · 1.41 Impact Factor
Show more